A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia, Age 0 to < 60 Months

Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in infants and young children with a diagnosis of achondroplasia.

Study Overview

• Status: Completed
• Conditions: Achondroplasia
• Intervention / Treatment: Drug: Placebo; Drug: BMN 111

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Westmead, New South Wales, Australia, 2145
      • The Children's Hospital at Westmead
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Murdoch Children's Research Institute
• Japan
  • Osaka, Japan
    • Osaka University Hospital
  • Saitama, Japan
    • Saitama Children's Medical Center
  • Tokushima, Japan
    • Tokushima University Hospital
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • Guy's and St. Thomas NHS Foundation Trust Evelina Children's Hospital
  • Sheffield, United Kingdom, S10 2TH
    • Sheffield Children's NHS Foundation Trust
• United States
  • California
    • Oakland, California, United States, 94609
      • Children's Hospital & Research Center Oakland
    • Torrance, California, United States, 90509
      • Harbor - UCLA Medical Center
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Alfred I. DuPont Hospital for Children
  • Georgia
    • Decatur, Georgia, United States, 30033
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37232-2578
      • Vanderbilt University Medical Center
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin, Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 1 year (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Diagnosis of achondroplasia (ACH), confirmed by genetic testing. If subjects had previous genetic testing, subjects must have a lab report from a certified laboratory with the study specific mutation documented.
2. Age 0 to < 60 months, at study entry (Day 1)
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth assessment in Study 111 901 immediately before screening, and have one documented measurement of height/body length a minimum of 6 months prior to the screening visit for 111-206. Cohort 3 subjects must have a minimum of 3 months of observation prior to treatment. This observational period can be obtained either (1) via prior enrollment in Study 111-901 or (2) via enrollment in this Study 111 206 for a minimum of 3 months of non-treatment observation prior to commencement of treatment.
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or ethics committee) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure
5. Willing and able to perform all study procedures as physically possible
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete the required training

Exclusion Criteria:

1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)
2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3)

3. Have any of the following:

   • Hypothyroidism or hyperthyroidism
   • Insulin-requiring diabetes mellitus
   • Autoimmune inflammatory disease (including celiac disease, systemic lupus erythematosus, juvenile dermatomyositis, scleroderma, etc.)
   • Inflammatory bowel disease
   • Autonomic neuropathy

4. Have a history of any of the following:

   • Renal insufficiency defined as serum creatinine > 2 mg/dL
   • Chronic anemia or Hgb <10.0 g/dL (based on screening clinical laboratory testing)
   • Baseline systolic blood pressure (BP) below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms e.g., dizziness, fainting) or recurrent symptomatic orthostatic hypotension

   • Cardiac or vascular disease, including the following

     • Cardiac dysfunction (abnormal echocardiogram determined to be clinically significant by principal investigator PI and medical monitor) at Screening Visit
     • Hypertrophic cardiomyopathy
     • Pulmonary hypertension
     • Congenital heart disease with ongoing cardiac dysfunction
     • Cerebrovascular disease
     • Aortic insufficiency or other clinically significant valvular dysfunction
     • Clinically significant atrial or ventricular arrhythmias
5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or Fridericia's corrected QT interval (QTc-F) >450 msec on screening ECG

6. Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention within 60 days of Screening as determined by the Investigator based on the following assessments

   • Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins)
   • Polysomnography (e.g., severe central sleep apnea)
   • MRI indicating presence of severe CMC or spinal cord damage
7. Have an unstable medical condition likely to require surgical intervention in the next 6 months, or planned spine or long-bone surgery (i.e., surgery involving significant disruption of bone cortex) during the study period
8. Have documented uncorrected Vitamin D deficiency: 25(OH)D <=15 ng/mL (37.5 nmol/L)
9. Require any other investigational product prior to completion of the study period
10. Have received another investigational product or investigational medical device within 30 days prior to the Screening visit
11. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time
12. Require current chronic therapy with antihypertensive medication or any medication that, in the investigator's judgment, may compromise the safety or ability of the subject to participate in this clinical study (Table 9.3.5.1)
13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the 6 months prior to screening, or long-term treatment (>3 months) at any time
14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months prior to screening

15. Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever had bone-related surgery with chronic complications

    NOTE: Subjects with prior cervicomedullary decompression may be allowed into Cohort 1 only after discussion and agreement with Medical Monitor.

16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the study period
17. Have had a fracture of the long bones or spine within 6 months prior to screening
18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin greater than upper limit of normal (ULN) at screening (except for subjects with a known history of Gilberts or newborns entering screening in Cohort 3)
19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea treatment (eg, Continuous positive airway pressure (CPAP) or sleep apnea-mitigating surgery) in the 2 months prior to screening
20. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy
21. Have known hypersensitivity to BMN 111 or its excipients
22. Have a history of hip surgery or severe hip dysplasia
23. Have a history of clinically significant hip injury in the 30 days prior to screening
24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head
25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the Investigator
26. Have a condition or circumstance that, in the view of the Investigator, places the subject at high risk for poor treatment compliance or for not completing the study
27. Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason

Inclusion Criteria for Cohort 3 Observation Period

1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, willing and able to provide written assent (if applicable) after the nature of the study has been explained and prior to performance of any research-related procedure.
2. Birth to <= 3 months of age at study entry.
3. Have ACH, documented by genetic testing
4. Are willing and able to perform all study procedures as physically possible

Exclusion Criteria for Cohort 3 Observation Period

1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)

2. Have any of the following disorders:

   • Hypothyroidism
   • Insulin-requiring diabetes mellitus
   • Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others)
   • Inflammatory bowel disease
   • Autonomic neuropathy
3. Have an unstable clinical condition likely to lead to intervention during the course of the study, including progressive cervical medullary compression

4. Have a history of any of the following:

   • Renal insufficiency
   • Anemia

5. Have a history of cardiac or vascular disease, including the following:

   • Cardiac dysfunction
   • Hypertrophic cardiomyopathy
   • Congenital heart disease
   • Cerebrovascular disease, aortic insufficiency
   • Clinically significant atrial or ventricular arrhythmias
6. Current treatment with antihypertensive medications, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, any medication that may impair or enhance compensatory tachycardia, drugs known to alter renal function that is expected to continue for the duration of the study
7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma is acceptable) in the previous 3 month
8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit
9. Have used any other investigational product or investigational medical device for the treatment of ACH or short stature
10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), during the study period.
11. Planned or expected to have limb-lengthening surgery during the study period.
12. Have any condition that, in the view of the Investigator, places the subject at high risk of poor compliance with the visit schedule or of not completing the study.
13. Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Daily subcutaneous injection of placebo	Drug: Placebo; Subcutaneous injection of 15 μg/kg of placebo daily, Subject to adjustment per protocol
Experimental: Active BMN111; Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN111 daily.	Drug: BMN 111; Subcutaneous injection of 15 μg/kg/day and/or 30 μg/kg/day of BMN 111 daily, subject to adjustment per protocol; Other Names: Vosoritide; Modified recombinant human C-type natriuretic peptide

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) by Severity Grade and Study Drug Treatment-emergent Adverse Events (TEAEs)	A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. Safety Population includes all sentinel and randomized participants in the FAS who received at least one dose of vosoritide or placebo in this study. Serious adverse event (SAE)	Up to Week 56 (Safety Follow-Up +/-7d)
Change From Baseline in Height Z-score at Week 52.	Z-Scores were derived using age-sex specific reference data (means and SDS) for average stature children per the Centers for Disease Control and Prevention. A height Z score of 0 would indicate that the subject's height is equal to the mean height for the average stature population of the same sex and age. A positive height Z score indicates that the subjects height is above the mean height for the average stature population of the same sex and age, whilst a negative height Z score indicates that the subjects height is below the mean height for the average stature population of the same sex and age. To conclude if the height Z score increases then this means the height deficit has decreased. standard deviation score (SDS). The primary efficacy analysis population was the subset of randomized participants in the FAS.	Baseline to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Height at Week 52	As a general rule, standing height/sitting height was used if participants were aged >= 24 months at baseline. Body length/crown to rump was used if participants were aged < 24 months at baseline. If body length was not measured and standing height was available, standing height was used.	Baseline to Week 52
Change From Baseline in Annualized Growth Velocity (AGV) at Week 52	AGV was derived over 12-month intervals starting from the baseline visit. Annualized growth velocity (AGV) = Standing Height at Date 2 - Standing Height at Date 1/Interval Length (Days) x 365.25. Difference in LS means were obtained from an analysis of covariance model.	Baseline to Week 52
Change From Baseline in Upper to Lower Body Segment Ratio at Week 52	Upper to Lower Body ratio=Sitting Height / (Standing Height - Sitting Height).	Baseline to Week 52
Change From Baseline in Other Growth Measures (Upper Body Length, Head Circumference, Arm Span, Upper Arm Length, Lower Arm Length, Lower Body Length, Upper Leg Length, Knee to Heel Length, and Tibial Length) at Week 52	Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm (Forearm) length, Lower Body Length, Upper Leg Length (Thigh), knee to heel length, and tibial length) at Week 52. Participants aged <24 months, body length and crown to rump length take precedence over standing height and sitting height. Participants aged <24 months at baseline and >=24 months at Week 52, body length and crown to rump length take precedence.	Baseline to Week 52
Change From Baseline in Other Body Proportion Ratios (Arm Span to Height Ratio, Upper Arm Length to Lower Arm [Forearm] Length Ratio, Upper Leg Length [Thigh] to Knee to Heel Length Ratio, and Upper Leg Length (Thigh) to Tibial Length Ratio) at Week 52	For Height: subjects aged < 24 months, body length takes precedence over standing height. Subjects aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.	Baseline to Week 52
Change From Baseline in Body Mass Index (BMI) at Week 52	Body Mass Index (BMI): For height used for BMI calculation, participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.	Baseline to Week 52
Change From Baseline in BMI Z-score at Week 52	The body mass index (BMI) Z-score represents the participant's BMI converted to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. The weight Z-score of 0 represents the mean BMI for age and sex of the reference population. A positive BMI Z-score means BMI is above the mean BMI for the average stature population of the same sex and age and a negative BMI Z-Score means BMI is below the mean BMI for the average stature population of the same sex and age. BMI Z-scores are derived only for participants aged 24 months or older, the change from baseline to Week 52 in BMI Z-score is summarized for Cohort 1 only as no participants in Cohort 2 or Cohort 3 were 24 months at baseline.	Baseline to Week 52
Change From Baseline in Weight Z-score at Week 52	The weight Z-score represents the participant's weight converted to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. The weight Z-score of 0 represents the mean weight for age and sex of the reference population. A positive weight Z-score means weight is above the mean weight for the average stature population of the same sex and age and a negative weight Z-Score means weight is below the mean weight for the average stature population of the same sex and age.	Baseline to Week 52
Change From Baseline in Infant Toddler Quality of Life (ITQoL) Scores at Week 52	97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health).	Baseline to Week 52
Change From Baseline in ITQoL-Behavior Scores at Week 52	97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). The number of subjects assessed in Cohort 3 Placebo is 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/ baseline. Hence, Mean and Standard Deviation (SD) are not applicable. Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.	Baseline to Week 52
Change From Baseline in ITQoL-Global Behavior Scores at Week 52	97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). A higher score indicates better global behaviour. The number of subjects assessed in Cohort 3 Placebo is 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/ baseline. Hence, Mean and Standard Deviation (SD) are not applicable. Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.	Baseline to Week 52
Change From Baseline in ITQoL-Getting On With Other Score at Week 52	97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). A higher score indicates better global health perceptions. The number of subjects assessed in Cohort 3 Placebo and Cohort 3 vosoritide are 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/baseline. Hence, Mean and Standard Deviation (SD) are not applicable. Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.	Baseline to Week 52
Change From Baseline in ITQoL-Health Score at Week 52	97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). A higher score indicates better global change in health. The number of subjects assessed in Cohort 3 Placebo is 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/ baseline. Hence, Mean and Standard Deviation (SD) are not applicable. Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.	Baseline to Week 52
Change From Baseline in Functional Independence Measure for Children (WeeFIM-II) Score at Week 52	The Pediatric Functional Independence Measure-II (WeeFIM®-II) is designed to measure functional independence of children between the ages of 6 months & 18 yrs who have physical or general developmental limitations. The WeeFIM-II is comprised of 3 domains that are rated by clinicians based on information obtained from parents/caregivers (self-care [score range 8 to 56], mobility [score range 8 to 35], & cognition [score range 8 to 35]) & provides a total score between 18 (worst) & 126 (Best). Higher score reflects higher level of independence. Performance of a child on each of individual items within WeeFIM is assigned to one of seven levels on an ordinal scale that represent function from complete & modified independence (levels 7 & 6) without a helping person to modified & complete dependence (levels 5 to 1) with a helping person. Functional Independence Measure (Wee-FIM-II) is only validated in children ages 6 months to 18 yrs. Therefore results for Cohort 3 is not summarized.	Baseline to Week 52
Change From Baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) Scores at Week 52	BSID-III is performance-based clinician-reported outcome assessment for use in children from 1 to 42 months (1 month to 3.5 years). individually administered by the trained clinician to the participant/child Scales include Cognitive subscale, Receptive and Expressive subscales, and Gross and Fine Motor subscales. The two language scales make up a composite Language Scale score and the Gross and Fine Motor subscales yield a composite Motor Scale score. In addition, there is a Social-Emotional Scale and Adaptive Behavior Scale, which is a questionnaire read and completed by parent or caregiver. Scores range from 0 to 2, and indicate mastery (2), emerging (1) or zero (not present) Each (sub)scale yields a total raw score, standardized according to the participant's chronological age (scaled scores)	Baseline to Week 52
Change From Baseline in Child Behaviour Checklist (CBCL) at Week 52	The CBCL is used as a screening tool for emotional or behavioral problems, measuring initial behavior severity, tracking changes in behavioral problems over the course of treatment, and treatment planning. The CBCL 1.5-5 years old consists of 100 questions, scored on a three-point Likert scale (0=Not True (as far as you know), 1= Somewhat or Sometimes True, 2=Very True or Often True). The scores for each individual question within a domain are summed to give a domain score. The CBCL uses a normative sample to create standard scores, which are scaled so that 50 is average with a standard deviation of 10, where higher scores indicate more emotional or behavioral issues. CBCL was waived for children < 18 months old. Therefore results for Cohort 3 is not summarized.	Baseline to Week 52
Change From Baseline in Bilateral X-rays of Lower Extremities at Week 52		Baseline to Week 52
Change From Baseline in Bilateral X-rays of Left/Right Tibia Bowing Angle at Week 52		Baseline to Week 52
Change From Baseline in Bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52		Baseline to Week 52 End point timeframe:
Change From Baseline in Bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52		Baseline to Week 52
Change From Baseline in X-ray of Lumbar Spine Vertebral Ratios at Week 52		Baseline to Week 52
Change From Baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52		Baseline to Week 52
Change From Baseline in X-ray of Lumbar Spine Sagittal Width and Week 52	Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.	Baseline to Week 52
Change From Baseline in X-ray of Lumbar Spine Angles at Week 52		Baseline to Week 52
Changes From Baseline in X-ray of Lumbar Spine Angle Changes: Number of Participants With an Increase in Lumbar Spine Angle at Week 52	Percentages were calculated using the total number of subjects in the safety population (N for each treatment group) as the denominator. All increases are comparing results at Week 52 relative to the baseline assessment.	Baseline to Week 52
MRI Parameter: Change From Baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.		Baseline to Week 52
MRI Parameter: Percentage Change From Baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.		Baseline to Week 52
MRI Parameter: Change From Baseline to Week 52 for Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level		Baseline to Week 52
MRI Parameter: Percentage Change From Baseline to Week 52 for Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level		Baseline to Week 52
MRI Parameter: Change From Baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus		Baseline to Week 52
MRI Parameter: Percentage Change From Baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus		Baseline to Week 52
Dual X Ray Absorptiometry (DEXA) Parameter: Change From Baseline to Week 52 for Whole Body Less Head Bone Mineral Content (BMC)		Baseline to Week 52
DEXA Parameter: Change From Baseline to Week 52 of Whole Body Less Head Bone Mineral Density (BMD)		Baseline to Week 52
DEXA Parameter: Change From Baseline to Week 52 of Whole Body BMC		Baseline to Week 52
DEXA Parameter: Change From Baseline to Week 52 of Lumbar Spine BMC		Baseline to Week 52
DEXA Parameter: Change From Baseline to Week 52 of Whole Body BMD		Baseline to Week 52
DEXA Parameter: Change From Baseline to Week 52 of Lumbar Spine BMD		Baseline to Week 52
Change From Baseline to Week 52 in Whole Body BMD Z-score	Hologic - Discovery Horizon Whole Body BMD Z-Score. Change in whole body bone mineral density (BMD) Z-score from baseline at 52 weeks indicates whether there has been a positive or negative change in BMD using a z-score generated by converting the participants BMD to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. A whole body BMD Z-score <-2 SD can indicate low bone density in children. The Whole Body BMD (bone mineral density) z-score compares the BMD to the average bone density of people of the same age, and sex as a comparator. A Z-score less than 0 means that the participant has a lower BMD than people in the same age and sex group, and could indicate a risk of osteopenia or osteoporosis.	Baseline to Week 52
Change From Baseline to Week 52 in Lumbar Spine BMD Z-Score	Hologic - Discovery Horizon Lumbar Spine BMD Z-Score Change in lumbar spine bone mineral density (BMD) Z-score from baseline at 52 weeks indicates whether there has been a positive or negative change in BMD using a z-score generated by converting the participants lumbar spine BMD to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. A BMD Z-score <-2 SD can indicate low bone density in the lumbar spine in children. The Lumbar Spine BMD (bone mineral density) z-score compares the BMD in the lumbar spine to the average spinal bone density of people of the same age, and sex as a comparator. A Z-score less than 0 means that the participant has a lower BMD than people in the same age and sex group, and could indicate a risk of osteopenia or osteoporosis of the spine.	Baseline to Week 52
Immunogenicity: Number of Participants With Incidence of Antibody Positivity at Scheduled Visits	Number of participants with Incidence of Antibody Positivity at Scheduled Visits for : total antibody (TAb), Neutralizing antibodies (NAb), atrial natriuretic peptide (ANP), B-type Natriuretic Peptide (BNP) & C-type natriuretic peptide (CNP). TAb Titer Positive, NAb Titer Positive, ANP Reactivity Positive, BNP Reactivity Positive & CNP Reactivity Positive. Day 1 is the baseline assessment result taken prior to first dose of study drug. Ever Positive = the number of participants with at least one positive sample result.	At Day 1, Week 3, Week 13, Week 26, Week 52, & Ever Positive.
Biomarker: Bone Specific Alkaline Phosphatase (BSAP) Overtime		At Baseline, Day 8, Week 6, Week 20, & Week 39.
Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)		Baseline to Week 52.
Biomarker: Plasma Cyclic Guanosine Monophosphate (cGMP) Change From Pre-Dose to Maximum Post-Dose at Week 52		Week 52 Pre-Dose to Week 52 Maximum Post-Dose.
Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM	Laboratory results up to 30 days after study drug discontinuation were included. Baseline is the last measurement prior to the initiation of study drug.	At Baseline, Day 8, Week 6, Week 20, & Week 39.
Change in Sleep Study Indices at Week 52	Sleep-testing device was used to assess presence & severity of sleep-disordered breathing by measurement of blood oxygen(O2)saturation,pulse rate,& airflow during overnight monitoring Episodes(Epi) of sleep apnea variables summarized as: Number(No.)of epi of apnea/hr(AI);No.of epi of hypopnea/hr(HI);No.of epi of obstructive apnea hypopneas/hr(AHI);No.of epi of obstructive apneas/hr(Obstructive Apnea Index);No.of epi of central apneas/hr(CAI);No.of desaturations/hr >=3% AHI is a marker of obstructive sleep apnea (OSA), scored as No.of apnea or hypopnea epi/hr, with AHI <=1/hr normal, 1< AHI<=5 mild,5< AHI <=10 moderate,& AHI>10/hr severe OSA. CAI reflects cervical cord compression at cervical-medullary junction, & is No. of epi of a pause in ventilation with no associated respiratory effort, with> 5 epi/hr abnormal.O2 desaturation index measures average No. of desaturation epi/hr, defined as decrease in O2 saturation of >=3% for at least 10sec, with(<8/hr normal & >=8/hr abnormal	Baseline to Week 52
PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52	Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞ excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.	At Day1, Week 13, Week 26, Week 39, & Week 52.
PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to Nominal 120 Minutes Postdose (AUC 0- 120 Min) at Day 01, Week 13, Week 26, Week 39, & Week 52		At Day 01, Week 13, Week 26, Week 39, & Week 52
PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of Last Measurable Concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52		At Day 01, Week 13, Week 26, Week 39, & Week 52
PK Parameter: Maximum Observed Plasma Concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52		At Day 01, Week 13, Week 26, Week 39, & Week 52
PK Parameter: Time to Reach Maximum Concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52		At Day 01, Week 13, Week 26, Week 39, & Week 52.
PK Parameter: Apparent Clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52	Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.	At Day 01, Week 13, Week 26, Week 39, & Week 52.
PK Parameter: Apparent Volume of Distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52	Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. V/F excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.	At Day 01, Week 13, Week 26, Week 39, & Week 52.
PK Parameter: Elimination Half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52	Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics. PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.	At Day 01, Week 13, Week 26, Week 39, & Week 52.

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Medical Director, MD, BioMarin Pharmaceutical

Publications and helpful links

Helpful Links

• U.S. FDA Resources
• NIH Genetics Home Reference related topics: Achondroplasia
• Description NIH Genetic and Rare Diseases Information Center resources: Achondroplasia

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2018
• Primary Completion (Actual): January 26, 2022
• Study Completion (Actual): January 26, 2022

Study Registration Dates

• First Submitted: June 14, 2018
• First Submitted That Met QC Criteria: July 10, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): June 13, 2024
• Last Update Submitted That Met QC Criteria: June 12, 2024
• Last Verified: June 1, 2024

More Information

Terms related to this study

• Keywords: Musculoskeletal Diseases; Osteochondrodysplasias; Genetic Diseases, Inborn; Bone Diseases; Bone Diseases, Developmental; Dwarfism; ACH; Skeletal Dysplasias; Natriuretic Agents; Natriuretic Peptide, C-Type; Physiological Effect of Drugs
• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Musculoskeletal Diseases; Bone Diseases; Dwarfism; Bone Diseases, Developmental; Osteochondrodysplasias; Achondroplasia; Physiological Effects of Drugs; Natriuretic Agents; Natriuretic Peptide, C-Type
• Other Study ID Numbers: 111-206; 2016-003826-18 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No